Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells
Daniel W. Sherbenou, … , Thomas G. Martin, Bin Liu
Daniel W. Sherbenou, … , Thomas G. Martin, Bin Liu
Published November 14, 2016
Citation Information: J Clin Invest. 2016;126(12):4640-4653. https://doi.org/10.1172/JCI85856.
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Research Article Hematology

Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells

Abstract

Multiple myeloma is incurable by standard approaches because of inevitable relapse and development of treatment resistance in all patients. In our prior work, we identified a panel of macropinocytosing human monoclonal antibodies against CD46, a negative regulator of the innate immune system, and constructed antibody-drug conjugates (ADCs). In this report, we show that an anti-CD46 ADC (CD46-ADC) potently inhibited proliferation in myeloma cell lines with little effect on normal cells. CD46-ADC also potently eliminated myeloma growth in orthometastatic xenograft models. In primary myeloma cells derived from bone marrow aspirates, CD46-ADC induced apoptosis and cell death, but did not affect the viability of nontumor mononuclear cells. It is of clinical interest that the CD46 gene resides on chromosome 1q, which undergoes genomic amplification in the majority of relapsed myeloma patients. We found that the cell surface expression level of CD46 was markedly higher in patient myeloma cells with 1q gain than in those with normal 1q copy number. Thus, genomic amplification of CD46 may serve as a surrogate for target amplification that could allow patient stratification for tailored CD46-targeted therapy. Overall, these findings indicate that CD46 is a promising target for antibody-based treatment of multiple myeloma, especially in patients with gain of chromosome 1q.

Authors

Daniel W. Sherbenou, Blake T. Aftab, Yang Su, Christopher R. Behrens, Arun Wiita, Aaron C. Logan, Diego Acosta-Alvear, Byron C. Hann, Peter Walter, Marc A. Shuman, Xiaobo Wu, John P. Atkinson, Jeffrey L. Wolf, Thomas G. Martin, Bin Liu

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Figure 2

Potent and selective activity of CD46-ADC on MM cells compared with BM stromal cells, with potentiation of ADC effect in the context of MM-stromal interactions.

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Potent and selective activity of CD46-ADC on MM cells compared with BM s...
(A) Confocal immunocytochemistry of MM1.R after 4 (left) and 18 (right) hours of incubation with anti-CD46 antibody (red). Late lysosomes shown with anti-LAMP1 antibody (green), and partial colocalization shown in merged panel (yellow). (B) Dose response for CD46-ADC inhibition of viability of MM cells compared with HS5 and BM61 BM stromal cells after 96-hour incubation (n = 3). NR: EC50 not reached due to lack of killing at the highest concentration tested. (C) Lack of effect of nonbinding control ADC until approximately 100 nM (n = 3). (D) Annexin V and PI staining of MM cell line INA-6 for 0–10 nM CD46-ADC, with apoptosis and death by 48 hours (representative data, n = 3). (E) Sensitivity of MM1.S cell line to CD46-ADC is increased in the presence of HS5, BM61, or HS27A BM stromal cells. EC50 was 2.25 nM on MM1.S alone and 0.77 nM, 0.92 nM, and 1.05 nM for MM1.S in the presence of HS5, HS27A, and BM61, respectively (data represent mean ± SEM, n = 3).